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Population Pharmacokinetic and Pharmacodynamic Analysis of a Class IC Antiarrhythmic, Pilsicainide, in Patients With Cardiac Arrhythmias
Author(s) -
Ogawa Ryuichi,
Kishi Ryoji,
Mihara Kiyoshi,
Takahashi Harumi,
Takagi Akihiko,
Matsumoto Naoki,
Masuhara Keisou,
Nakazawa Kiyoshi,
Miyake Fumihiko,
Kobayashi Shinichi,
Echizen Hirotoshi
Publication year - 2006
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270005283281
Subject(s) - medicine , pharmacodynamics , pharmacokinetics , atrial fibrillation , cardiology , population , nonmem , torsades de pointes , sodium channel blocker , anesthesia , qt interval , sodium channel , sodium , chemistry , environmental health , organic chemistry
Population pharmacokinetics (PK) of a sodium channel—blocking antiarrhythmic, pilsicainide, was studied using the nonlinear mixed‐effects modeling technique in 91 patients with cardiac arrhythmias (80 suspected Brugada syndrome [BrS] and 11 with atrial fibrillation) who received an intravenous infusion of 10 mg of the drug. Population pharmacodynamic (PD) analysis was also performed using an effect compartment model. PD responses were assessed by changes in electrocardiogram (ECG) pattern (BrS‐like elevation of ST‐segment) and conduction parameters. The final PK model showed that gender (values were 50% lower in women than in men) and creatinine clearance were significant ( P < .01) covariates of weight‐normalized systemic clearance of pilsicainide. Patients who showed a BrS‐like ECG pattern after the drug administration also showed a significantly ( P < .01) greater prolongation in His‐Purkinje conduction compared to the remaining patients. In conclusion, female gender, renal dysfunction, and the drug‐induced BrS‐like ECG morphology may be associated with augmented ECG responses to pilsicainide.